Learning by failing: ideas and concepts to tackle γ-secretases in Alzheimer's disease and beyond

B De Strooper… - Annual review of …, 2015 - annualreviews.org
γ-Secretases are a group of widely expressed, intramembrane-cleaving proteases involved
in many physiological processes. Their clinical relevance comes from their involvement in …

Alzheimer presenilin-1 mutations dramatically reduce trimming of long amyloid β-peptides (Aβ) by γ-secretase to increase 42-to-40-residue Aβ

MA Fernandez, JA Klutkowski, T Freret… - Journal of Biological …, 2014 - ASBMB
The presenilin-containing γ-secretase complex produces the amyloid β-peptide (Aβ) through
intramembrane proteolysis, and> 100 presenilin mutations are associated with familial early …

Toward structural elucidation of the γ-secretase complex

H Li, MS Wolfe, DJ Selkoe - Structure, 2009 - cell.com
γ-Secretase is an intramembrane protease complex that mediates the Notch signaling
pathway and the production of amyloid β-proteins. As such, this enzyme has emerged as an …

Dissociation between the processivity and total activity of γ-secretase: implications for the mechanism of Alzheimer's disease-causing presenilin mutations

O Quintero-Monzon, MM Martin, MA Fernandez… - Biochemistry, 2011 - ACS Publications
The amyloid β-peptide (Aβ), strongly implicated in the pathogenesis of Alzheimer's disease
(AD), is produced from the amyloid β-protein precursor (APP) through consecutive …

Zinc and copper differentially modulate amyloid precursor protein processing by γ-secretase and amyloid-β peptide production

H Gerber, F Wu, M Dimitrov, GMG Osuna… - Journal of Biological …, 2017 - ASBMB
Recent evidence suggests involvement of biometal homeostasis in the pathological
mechanisms in Alzheimer's disease (AD). For example, increased intracellular copper or …

Cryoelectron microscopy structure of purified γ-secretase at 12 Å resolution

P Osenkowski, H Li, W Ye, D Li, L Aeschbach… - Journal of molecular …, 2009 - Elsevier
γ-Secretase, an integral membrane protein complex, catalyzes the intramembrane cleavage
of the β-amyloid precursor protein (APP) during the neuronal production of the amyloid β …

Alzheimer's disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

M Dimitrov, JR Alattia, T Lemmin, R Lehal… - Nature …, 2013 - nature.com
Pathological amino-acid substitutions in the amyloid precursor protein (APP) and chemical γ-
secretase modulators affect the processing of APP by the γ-secretase complex and the …

Alzheimer's Disease-Linked Mutations in Presenilin-1 Result in a Drastic Loss of Activity in Purified γ-Secretase Complexes

M Cacquevel, L Aeschbach, J Houacine, PC Fraering - PloS one, 2012 - journals.plos.org
Background Mutations linked to early onset, familial forms of Alzheimer's disease (FAD) are
found most frequently in PSEN1, the gene encoding presenilin-1 (PS1). Together with …

The Alzheimer's disease γ-secretase generates higher 42: 40 ratios for β-amyloid than for p3 peptides

G Siegel, H Gerber, P Koch, O Bruestle, PC Fraering… - Cell reports, 2017 - cell.com
Alzheimer's disease is characterized by intracerebral deposition of β-amyloid (Aβ). While Aβ
40 is the most abundant form, neurotoxicity is mainly mediated by Aβ 42. Sequential …

A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor

L Liu, L Ding, M Rovere, MS Wolfe, DJ Selkoe - Journal of Cell Biology, 2019 - rupress.org
Intramembrane proteolysis of transmembrane substrates by the presenilin–γ-secretase
complex is preceded and regulated by shedding of the substrate's ectodomain by α-or β …